# IL4I1⁺ Macrophages and TDO2⁺ Myofibroblasts Drive AhR‐Mediated Immunosuppression and Ferroptosis Resistance in Solid Predominant Lung Adenocarcinoma

## TL;DR

This study identifies immune cells and fibroblasts that create a resistant environment in a specific type of lung cancer, offering new treatment strategies.

## Contribution

The novel contribution is the discovery of IL4I1⁺ TAMs and TDO2⁺ myCAFs driving immunosuppression and resistance to therapy in solid predominant LUAD.

## Key findings

- IL4I1⁺ TAMs and TDO2⁺ myCAFs co-localize in peritumoral stroma, forming an immune-excluded niche.
- AhR signaling in these cells promotes T cell exhaustion and resistance to anti-PD-1 therapy.
- Combining AhR antagonists, ferroptosis inducers, and anti-PD-1 agents shows potent antitumor efficacy.

## Abstract

Lung adenocarcinoma (LUAD) displays marked intratumoral heterogeneity with distinct histological patterns. The solid pattern representing poorly differentiated LUAD is linked to poor prognosis and therapeutic resistance. To uncover underlying mechanisms, we integrate bulk and single‐cell RNA sequencing and identify a preferential enrichment of interleukin 4 induced 1 (IL4I1)‐expressing tumor‐associated macrophages (TAMs) and tryptophan 2,3‐dioxygenase (TDO2)‐expressing myofibroblastic cancer‐associated fibroblasts (myCAFs) in a solid pattern of LUAD. Spatial transcriptomics reveals their co‐localization in peritumoral stroma, forming an immune‐excluded niche. Mechanistically, TDO2⁺ myCAFs promoted monocyte‐to‐IL4I1⁺ TAM differentiation via the kynurenine‐aryl hydrocarbon receptor (AhR) axis. Tryptophan metabolomic landscapes confirm that IL4I1⁺ TAMs and TDO2⁺ myCAFs enhance tryptophan degradation and accumulation of AhR ligands (e.g., kynurenine, indole‐3‐carboxaldehyde), contributing to CD8⁺ T cell exhaustion and anti‐PD‐1 therapeutic resistance. IL4I1⁺ TAMs and TDO2⁺ myCAFs conformably mediate ferroptosis resistance through the AhR‐NRF2‐GPX4‐SLC7A11 pathway. Notably, AhR antagonist CH‐223191 restores ferroptosis sensitivity of tumor cells. A triple therapy combining CH‐223191, ferroptosis inducer (Imidazole ketone erastin or RSL3), and anti‐PD‐1 agent demonstrates superior efficacy and safety in vivo. Together, our findings demonstrate that IL4I1⁺ TAMs and TDO2⁺ myCAFs synergistically establish an immunosuppressive, ferroptosis‐resistant niche via AhR signaling in solid predominant LUAD and offer promising therapeutic strategies to reprogram the tumor microenvironment.

Solid predominant lung adenocarcinoma exhibits an immune‐excluded, ferroptosis‐resistant niche enriched with IL4I1⁺ TAMs and TDO2⁺ myCAFs. Spatial and multi‐omics analyses reveal AhR‐driven crosstalk that promotes T cell exhaustion and therapy resistance. Blocking AhR with CH‐223191 restores ferroptosis sensitivity, and its combination with ferroptosis inducers and anti‐PD‐1 achieves potent antitumor efficacy.